This invention relates to a pharmaceutical agent for the prevention or treatment of any of the following conditions in mammals: atherosclerosis, thrombosis, unwanted high levels of free radicals, unwanted long fibrin clot lysis times, unwanted fibrin clot characteristics, unwanted high levels of free fatty acids and obesity and the use thereof.
It is generally known that atherosclerosis is primarily caused by increased levels of cholesterol in human beings and that thrombosis is caused by the polymerisation of fibrin to form fibrin clots.
Low density lipoprotein cholesterol (LDL-C), occurring in relatively high concentrations, is particularly responsible for an increase in cardiovascular disease, especially when the LDL-C is oxidised by free radicals such as lipid peroxides. Although it is has been reported that dietary fibre can modify lipid metabolism in man, no effects of fibre, fibre components or metabolites thereof on lipid peroxidation have been reported.
It is further known that fermentable non-starch polysaccarides such as pectin, are fermented in the colon of a mammal to short chain fatty acids or derivatives thereof, such as acetate, propionate and butyrate. The butyrate is absorbed by the colon cells while the propionate and acetate move to the liver. The propionate is retained in the liver while the acetate is distributed throughout the cells and plasma of the mammal.
A high level of free fatty acids in vivo is unfavorable because it has a negative influence on the metabolism of a mammal in that it is atherogenic and promotes insulin resistance.
U.S. Pat. No. 4,870,105 discloses a method of administering orally to an individual a pharmaceutical composition which includes calcium acetate in sufficient quantities to effectively bind phosphorus present in food and beverages consumed by the individual to prevent its absorption in the intestines (column 2, lines 14 to 19). The calcium acetate is administered in a gelatin coating. The gelatin is hydrolyzed and the acetate absorbed in the intestines. The gelatin is therefore not resistant to digestion and solution in the stomach and small intestines of a mammal and releases the calcium acetate in the stomach and small intestines where it is absorbed. A disadvantage of the composition disclosed in U.S. Pat. No. 4,870,105 is that it is not suitable for use as a pharmaceutical agent for the prevention or treatment of atherosclerosis, thrombosis, high levels of free radicals, long fibrin dot lysis times, unwanted fibrin clot characteristics such as fibrin networks comprising thin and dense fibres with low permeability, high levels of free fatty acids and obesity (the ailments).
U.S. Pat. No. 4,721,716 discloses the coating of butyric acid with an enteric coating such as ethyl cellulose and the treatment of food allergies by oral ingestion of such coated butyrate. The ethyl cellulose restrains the release of butyric acid in the stomach, but is dissolved in the small intestines so that, as a result, the butyric acid is released in the small intestines and not in the colon of the individual. A disadvantage of the composition disclosed in U.S. Pat. No. 4,721,716 is that it is not suitable for treating the above ailments.
EP 0 616 802 discloses an oral pharmaceutical preparation of a type released in the intragastriontestinal tract and prepared by filling a chitosan capsule with a solid preparation containing a principal agent and a solid organic acid. The chitosan forms an enteric coating on the surface of the capsule. The organic acid comprises citric acid, tartaric acid, malic acid, succinic acid, adipic acid, benzoic acid and the like (page 5, lines 10 and 11). A disadvantage of the composition disclosed in EP 0 616 802, is that it is not suitable for the prevention or treatment of the above ailments.
WO 90 04334 discloses the administration to the colon of xcex2-glucan in tablet or powder form via the stomach end small intestines. The xcex2-glucan is partially fermented by endogenous colonic bacteria to short chain fatty acids (predominantly acetate, propionate and butyrate). Some of the disadvantages of the composition disclosed in WO 90 04334 are that the amount of xcex2-glucan that are needed to be administered in order to obtain a significant therapeutic result is relatively large and dependant on an uncertain factor such as microbiological intervention. It is therefore not suitable for treating the above ailments.
It is an object of the present invention to provide a novel pharmaceutical agent for the prevention or treatment of any of the following conditions in mammals: atherosclerosis, thrombosis, unwanted high levels of free radicals, unwanted long fibrin clot lysis times, unwanted fibrin clot characteristics, unwanted high levels of free fatty acids and obesity and the use thereof.
According to the invention a pharmaceutical agent for the prevention or treatment of any of the following conditions in mammals: atherosclerosis, thrombosis, high levels of free radicals, long fibrin clot lysis times, unwanted fibrin clot characteristics such as fibrin networks comprising thin and dense fibres with low permeability, high levels of free fatty acids and obesity, is provided which comprises a short chain fatty acid selected from the group comprising acetic acid and propionic acid, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable protective coating which is resistant to digestion and solution in the stomach and small intestine of a mammal, but digestible or soluble in the colon of a mammal.
Preferably the pharmaceutically acceptable salt of the short chain fatty acid is the calcium salt thereof.
The protective coating may comprise a natural or synthetic resin such as shellac.
The pharmaceutical agent preferably comprises calcium acetate in the form of a capsule, tablet or pill coated with such a resin.
Preferably the agent comprises between 0.1 grams and 100.0 grams of the acetate.
According to another aspect of the invention a method for the treatment or prevention of any one or more of said conditions in a mammal includes the step of administering to the colon of a mammal via the digestive tract an agent comprising a short chain fatty acid selected from the group comprising acetic acid and propionic acid or a pharmaceutically acceptable salt thereof.
According to another aspect of the invention there is provided the use of an agent comprising a short chain fatty acid selected from the group comprising acetic acid and propionic acid or a pharmaceutically acceptable salt thereof in a method for the treatment or prevention of any one or more of said conditions in mammals.
According to another aspect of the invention there is provided the use of an agent comprising a short chain fatty acid selected from the group comprising acetic acid and propionic acid or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method for the treatment or prevention of any one or more of said conditions in mammals.
Further according to the invention, the aforesaid method includes the step of administering the agent orally in the form of a capsule, pill or tablet coated with a protective coating which is resistant to digestion and solution in the stomach and small intestine of a mammal, but soluble or digestible in the colon of said mammal.
Still further according to the invention the pharmaceutically acceptable salt is the calcium salt of the short chain fatty acid.
Still further according to the invention the protective coating comprises a natural or synthetic resin such as shellac.
Applicant has found that the aforesaid clinical effects can be attained by administering the agent to a human being in an amount of between 0.1 gram and 100.0 gram at least once a day.
The invention will now be described further by way of the following non-limiting examples.
The codes used in the examples denote the following: